Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the present invention relates to certain novel compounds, or pharmaceutically acceptable salts thereof, which possess anticancer activity and are therefore potentially useful in methods of treating the human or animal body.
• the present invention also relates to methods for the manufacture of the compounds, pharmaceutical compositions containing them and their use in methods of treatment, such as for the manufacture of medicaments for the prevention or treatment of cancer in warm-blooded animals such as humans, including For the prevention or treatment of estrogen receptor-dependent or estrogen receptor-mediated diseases.
• the present invention also relates to compounds that are selective down-modulators of the estrogen receptor.
• Estrogen receptor belongs to the steroid hormone receptor, including two subtypes, ER ⁇ and ER ⁇ . ER is involved in the regulation and development of the female reproductive tract; in cancers such as breast cancer, tumor growth is related to the action of estrogen and ER receptors, for example, the expression of ER is elevated in most breast cancer patients.
• SERMs selective estrogen receptor modulators
• WO2017/182493A1 also discloses a SERM compound.
• the inventors of the present invention found that the compound represented by the formula (I) has the basic structure of tetrahydrooxazoloisoquinolin-one, which has significant ER degradation activity, and therefore unexpectedly has significantly better properties than the prior art Compounds are known for their ER inhibitory activity; such compounds also have excellent metabolic stability. Therefore, the compounds of the present invention can be used for the treatment of estrogen receptor-dependent or estrogen receptor-mediated diseases, thereby completing the present invention.
• the present invention relates to the following.
• One aspect of the present invention provides a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof:
• Z 1 is selected from CR a R b , C(O) and a bond
• Z 2 is selected from O, S, NR c , C(O) and bonds, or C 1 -C 6 alkylene, O-(C 1 -C optionally substituted with one or more of the same or different R d 6 alkylene) or NH-(C 1 -C 6 alkylene);
• Cy 1 is selected from C 6-14 arylene, C 3-8 cycloalkylene, C 5-14 heteroarylene, C 3-14 heterocycloalkylene, C 3-14 heterocycloalkenylene, each of which is optionally substituted with a group selected from the group consisting of halogen atoms, hydroxy, amino, cyano and C 1-6 alkyl or C 1-6 alkoxy optionally substituted with halogen atoms;
• Cy 2 is selected from bond, C 3-10 cycloalkylene, C 3-14 heterocycloalkylene, each of which is optionally substituted with a group selected from the group consisting of halogen atoms (including F, Cl, Br or I atoms) ), hydroxyl, amino, cyano, and C 1-6 alkyl or C 1-6 alkoxy optionally substituted by halogen atoms;
• halogen atoms including F, Cl, Br or I atoms
• R 1 and R 2 are each independently H, halogen atom, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkenylamino , C 3 -C 8 cycloalkyl, said C 1-6 alkyl, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkenylamino or C 3 -C 8 cycloalkyl optionally substituted by one or more groups selected from halogen atoms, hydroxy, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, cyano or oxo;
• R 4 is H, halogen atom, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkylamino, amino C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkene amino, C 3 -C 8 cycloalkyl, the C 1-6 alkyl, C 1-6 alkylamino, amino C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl Amino or C 3 -C 8 cycloalkyl is optionally replaced by one or more selected from halogen atoms, hydroxyl, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, cyano, oxo group, C 6-14 aryl, C 5-14 heteroaryl, C 3-14 heterocycloalkylene or
• R 4 is H, halogen atom, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkenylamino, C 3 -C 8 cycloalkyl, said C 1-6 alkyl, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkenylamino or C 3 -C 8 cycloalkyl are optionally Substituted with one or more groups selected from halogen atom, hydroxyl, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, cyano or oxo;
• R 3 is -(CR e R f ) m -CR 31 R 32 R 33 , wherein m is 1, 2 or 3;
• R 31 , R 32 and R 33 are independently selected from: H, a C 1-6 alkyl group, a halogen atom, a cyano group, and R 31 and R 32 may together form a C 3-8 cycloalkylene group, the C 1-8 6 alkyl and C 3-8 cycloalkylene are optionally substituted by hydroxyl, cyano, amino or halogen atoms;
• R a , R b , R c , R d , Re and R f are each independently H, a halogen atom, a hydroxyl group, an amino group, a cyano group, a C 1-6 alkyl group optionally substituted with a halogen atom.
• heteroaryl/heteroarylene, heterocycloalkyl/heterocycloalkylene, heterocycloalkenyl/heterocycloalkenyl contain 1-4 selected from N, O, S
• the heteroatoms are used as ring constituent atoms.
• the cycloalkyl/cycloalkylene, heterocycloalkyl/heterocycloalkylene, heterocycloalkenyl/heterocycloalkenylene may be monocyclic, bicyclic or tricyclic (preferably monocyclic or bicyclic) ring systems, wherein bicyclic or tricyclic ring systems include spiro, bridged or fused rings.
• the aryl/arylene and heteroaryl/heteroarylene may be monocyclic, fused bicyclic or fused tricyclic (preferably monocyclic or fused bicyclic) ring systems, and wherein the fused bicyclic or The fused tricyclic ring system may contain non-aromatic ring structures.
• the halogen atoms are selected from F, Cl, Br or I atoms.
• Z 1 is selected from CR a R b , C(O) and a bond
• Z 2 is selected from O, S, NR c , C(O) and bonds, or C 1 -C 6 alkylene, O-(C 1 -C optionally substituted with one or more of the same or different R d 6 alkylene) or NH-(C 1 -C 6 alkylene);
• Cy 1 is selected from C 6-14 arylene (preferably C 6-10 arylene) and C 5-14 heteroarylene (preferably C 5-10 heteroarylene), each of which is optionally selected from the following The group substitution of: halogen atom, and C 1-6 alkyl or C 1-6 alkoxy optionally substituted by halogen atom;
• Cy 2 is selected from bonds, C 3-10 cycloalkylene (preferably C 3-8 cycloalkylene), C 3-14 heterocycloalkylene (preferably C 3-10 heterocycloalkylene);
• R 1 and R 2 are each independently H or a C 1-6 alkyl group, and the C 1-6 alkyl group is optionally substituted by one or more groups selected from halogen atoms, hydroxyl groups or cyano groups;
• R 3 is -(CR e R f ) m -CR 31 R 32 R 33 , wherein m is 1, 2 or 3;
• R 31 , R 32 and R 33 are independently selected from: H, a C 1-6 alkyl group, a halogen atom, a cyano group, and R 31 and R 32 may together form a C 3-8 cycloalkylene group, the C 1-8 6 alkyl and C 3-8 cycloalkylene are optionally substituted by hydroxyl, cyano, amino or halogen atoms;
• R a , R b , R c , R d , Re , R f are each independently H or a halogen atom
• R 4 is C 1-6 alkyl, C 1-6 alkylamino, amino C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenylamino, C 3 -C 8 cycloalkyl,
• the C 1-6 alkyl, C 1-6 alkylamino, amino C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenylamino or C 3 -C 8 cycloalkyl are optional by one or more selected from halogen atom, hydroxyl, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, cyano, oxo and
• R 4 is C 1-6 alkyl, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkenylamino, C 3 -C 8 cycloalkyl, the C 1- 6 alkyl, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkenylamino, or C 3 -C 8 cycloalkyl optionally by one or more selected from halogen atoms, hydroxyl, amino , C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, cyano or oxo group substitution.
• Z 1 is the key
• Z 2 is selected from -O-CH 2 -CH 2 -, -O-CH 2 -, -NH-CH 2 -CH 2 -, -NH-CH 2 -, -NH- or -O-;
• Cy 1 is a C 6-10 arylene group (preferably phenyl) and a C 5-10 heteroarylene group (preferably pyridyl), which are optionally replaced by a halogen atom (preferably F) or a C 1-6 alkoxy group (preferably methoxy) substituted;
• Cy 2 is selected from bond, azetidine, pyrrolidylene, piperazinylene,
• R 1 is C 1-6 alkyl (preferably methyl);
• R 2 is H
• R 3 is -CH 2 -CR 31 R 32 R 33 ;
• R 31 , R 32 and R 33 are independently selected from: H, C 1-6 alkyl (preferably methyl) optionally substituted with hydroxy or halogen atom (preferably F), halogen atom (preferably F), cyano, and R 31 and R 32 may together form a C 3-8 cycloalkylene group (preferably cyclopropylidene) optionally substituted by a hydroxyl group or a halogen atom (preferably F);
• R 4 is optionally selected from halogen atom (preferably F), oxo group, C 1-6 alkylamino (preferably methylamino), (C 1-6 alkyl) 2 amino (preferably dimethylamino) ,and
• Cy 2 is selected from bond, azetidine, pyrrolidylene, and R 4 is optionally selected from halogen atom (preferably F), oxo, C 1-6 alkylamino (preferably methylamino) and (C 1-6 alkyl) 2 amino (preferably dimethylamino) groups substituted C 1-6 alkyl, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkenylamino.
• halogen atom preferably F
• oxo oxo
• C 1-6 alkylamino preferably methylamino
• C 1-6 alkyl 2 amino preferably dimethylamino
• Z 1 is the key
• Z 2 is selected from -NH- or -O-;
• Cy 1 is phenyl or pyridyl (preferably phenyl) optionally substituted with F or methoxy;
• Cy 2 is selected from azetidine, pyrrolidylene, piperazinylene;
• R 1 is methyl
• R 2 is H
• R 3 is -CH 2 -CR 31 R 32 R 33 ;
• R 31 and R 32 are each F, or R 31 and R 32 together form a cyclopropylene
• R 33 is selected from: H, hydroxymethyl, fluoromethyl, preferably selected from F, hydroxymethyl, fluoromethyl;
• R 4 is F-(CH 2 ) 3 -or
• Cy 2 is selected from azetidine and pyrrolidylene, and R 4 is F-(CH 2 ) 3 -.
• the compounds of formula (I) of the present invention are in the form of stereoisomers, eg, the carbon at position 1 of the tetrahydroisoquinoline ring (ie, the carbon to which Z is attached) may be in the S configuration , and/or the carbon at position 3 (ie, the carbon to which R 1 is attached) may be in the R configuration.
• the present invention relates to the following compounds or stereoisomers or pharmaceutically acceptable salts thereof:
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising any one or more of the foregoing compounds of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the present invention relates to the use of a compound of the present invention in the manufacture of a medicament for the treatment of an estrogen receptor-dependent or estrogen receptor-mediated disease in a mammal.
• Step 3 Synthesis of (R)-7-2-aminopropyl)(2,2,2-trifluoroethyl-3-tritylbenzo[d]oxazol-2(3H)-one
• Step 6 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2, 3,6,7,8,9-Six Synthesis of Hydroxazolo[5,4-f]isoquinolin-6yl)pyridin-3-yl)amino)azetidine-1-carboxylic acid tert-butyl ester
• Step 7 (6S,8R)-6-(5-(azetidine-3-amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl yl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one
• Trifluoroacetic acid (9.00 mL) and water (1.00 mL) were added to 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2) at 0°C -Trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6yl)pyridin-3-yl ) amino) azetidine-1-carboxylic acid tert-butyl ester (120 mg, 154 ⁇ mol, 1 eq), the mixture was reacted at 20° C. for 2 hours, and the completion of the reaction was monitored by TLC.
• Step 8 (6S,8R)-6-(5-((1-(3-fluoropropane)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl -Synthesis of 7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (compound 5)
• Step 1 (S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl Base-2,3,6,7,8,9- Synthesis of tert-butyl hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate
• Trifluoroacetic acid (1.54 g, 13.4 mmol, 997 uL, 87.3 eq) was added to (S)-3-((6-((6S,8R)-8-methane dissolved in dichloromethane (2 mL) at 0 °C yl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4 -f] isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 154 ⁇ mol, 1 eq) at 20°C for 2 hours, TLC and LCMS monitoring the reaction Finish.
• Step 1 (6S,8R)-6-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl) )-3-trityl -2,3,6,7,8,9-Hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)-2,6-diazaspiro[3.3]heptane- Synthesis of tert-butyl 2-carboxylate to make
• Step 3 (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptane-2-yl)benzene base)-8-methyl Synthesis of -7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one
• Step 4 (6S,8R)-6-(2,6-difluoro-4-(6-(2-fluoroethyl)-2,6-diazaspiro[3.3]heptane-2-yl)benzene base)-8-methyl Resolution of -7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one ( Compound 8)
• Example 13-15 were synthesized; the compound in Example 5, step 3, namely “(R) -7-2-Aminopropyl)(2,2,2-trifluoroethyl-3-tritylbenzo[d]oxazol-2(3H)-one ⁇ as starting material, the following Example 10 was synthesized -12, 16, 18, 25; the compound of step 4 in Example 1 is -(R)-7-(2-aminopropyl)-3-tritylbenzo[d]o
• Step 3 (6S,8R)-6-(4-((1-(3-Fluoropropyl)azetidin-3-yl)amino)-2-methoxyphenyl)-8-methyl yl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline-2( Synthesis of 3H)-ketone
• Trifluoroacetic acid (15.4 g, 135 mmol) and (6S,8R)-6-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)-2-methoxy phenyl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4- f]
• Isoquinolin-2(3H)-one (1 g, 1.31 mmol) was dissolved in water (1 mL), and the reaction solution was reacted at 20° C. under nitrogen protection for 1 hour. The end of the reaction was detected by LCMS.
• Step 6 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2, 3,6,7,8,9-Hexahydrooxazolo[5,4-f]isoquinolin-6yl)pyridin-3-yl)amino)azetidine-1-carboxylate tert-butyl ester synthesis
• Step 7 (6S,8R)-6-(5-(azetidin-3-ylamino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl yl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one
• Trifluoroacetic acid (9.00 mL) and water (1.00 mL) were added to 3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2) at 0°C -Trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6yl)pyridin-3-yl ) amino) azetidine-1-carboxylic acid tert-butyl ester (120 mg, 154 umol, 1 eq), the mixture was reacted at 20° C. for 2 hours, and the completion of the reaction was monitored by TLC.
• Step 8 (6S,8R)-6-(5-((1-(3-fluoropropane)azetidin-3-yl)amino)pyridin-2-yl)-8-methyl-7- Synthesis of (2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one
• Step 4 (6S,8R)-6-(3-Fluoro-5-((1-(3-Fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8- Synthesis of methyl-7-(2,2,2-trifluoromethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one
• Trifluoroacetic acid (2.02 g, 17.6 mmol) was dissolved in water (0.05 mL) and (6S,8R)-6-(3-fluoro-5-((1-(3-fluoropropyl)azetidine) was added Alkyl-3-yl)amino)pyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9- In tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (120 mg, 138 umol), the reaction was carried out at 20°C for 5 hours under nitrogen protection. LCMS detected the end of the reaction.
• Step 5 (6S,8R)-6-(3-Fluoro-5-((1-(3-Fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-8- Synthesis of methyl-7-(2,2,2-trifluoromethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one
• Step 1 (6S,8R)-6-(5-bromo-3-methoxypyridin-2-yl)-8-methyl-7-(2,2,2-trifluoroethyl)-6, Synthesis of 7,8,9-Tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one
• Step 3 (6S,8R)-6-(5-((1-(3-Fluoropropyl)azetidin-3-yl)amino)-3-methoxypyridin-2-yl) -8-Methyl-7-(2,2,2-trifluoroethyl)-3-trityl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinoline Synthesis of Lin-2(3H)-ones
• Step 1 (S)-3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl tert-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylic acid Synthesis of Butyl Ester
• Trifluoroacetic acid (1.54 g, 13.4 mmol, 997 uL, 87.3 eq) was added to (S)-3-((6-((6S,8R)-8-methane dissolved in dichloromethane (2 mL) at 0 °C yl-2-oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4 -f] isoquinolin-6-yl)pyridin-3-yl)oxy)pyrrolidine-1-carboxylate tert-butyl ester (120mg, 154umol, 1eq) at 20°C for 2 hours, monitored by TLC and LCMS The reaction is complete.
• Step 1 (S)-3-(3-methoxy-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)- 3-Trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidine-1-carboxylic acid tert.
• Step 3 (6S,8R)-6-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)-2-methoxyphenyl)-8 -Methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one synthesis
• Step 2 (6S,8R)-7-((1-Fluorocyclopropyl)methyl)-6-(4-((1-(3-Fluoropropyl)azetidin-3-yl) ) Amino)-2-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one
• Step 1 3-((3,5-Difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3- Trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)amino)azetidine-1- Synthesis of tert-butyl formate
• Step 2 (6S,8R)-6-(4-(azetidin-3-ylamino)-2,6-difluorophenyl)-8-methyl-7-(2,2,2 Synthesis of -trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one
• Trifluoroacetic acid (15.5 g, 135 mmol) was dissolved in water (1 mL) and 3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7- (2,2,2-Trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinoline-6- (400 mg, 493 umol) in tert-butyl) phenyl) amino) azetidine-1-carboxylate (400 mg, 493 umol), and reacted under nitrogen protection at 20°C for 2 hours.
• LCMS detected the end of the reaction.
• Step 3 (E)-4-(3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-tri Fluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)amino)azetidine-1 -base)-N,N-dimethylbut-2-enamide synthesis
• Example 36 (6S,8R)-6-(4-((1-Acryloylazetidin-3-yl)amino)-2,6-difluorophenyl)-8-methyl-7 -(2,2,2-Trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one (Compound 36)
• Step 1 (6S,8R)-6-(4-((1-acryloylazetidin-3-yl)amino)-2,6-difluorophenyl)-8-methyl-7- Synthesis of (2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one
• Step 1 (R)-3-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl) -3-Trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidine-1-carboxylic acid Synthesis of tert-butyl ester
• Trifluoroacetic acid (6.16 g, 54.0 mmol) was dissolved in water (0.4 mL) and (R)-3-(3,5-difluoro-4-((6S,8R)-8-methyl-2- Oxo-7-(2,2,2-trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]iso quinolin-6-yl)phenoxy)pyrrolidine-1-carboxylate tert-butyl ester (503mg, 609umol), react under nitrogen protection at 20°C for 2 hours. LCMS detected the end of the reaction.
• Step 3 (E)-4-((R)-3-((3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2, 2-Trifluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenoxy)pyrrolidin-1-yl Synthesis of )-N,N-dimethylbut-2-enamide
• Step 1 (6S,8R)-6-(4-(((R)-1-acryloylpyrrolidin-3-yl)oxy)-2,6-difluorophenyl)-8-methyl- Synthesis of 7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydrooxazolo[5,4-f]isoquinolin-2(3H)-one
• Step 1 4-(3,5-Difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-3-tri Synthesis of Benzyl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester
• Trifluoroacetic acid (12.3 g, 107 mmol) was dissolved in water (0.1 mL) and 4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7- (2,2,2-Trifluoroethyl)-3-trityl-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinoline-6- (413 mg, 500 umol) in tert-butyl) phenyl) piperazine-1-carboxylate (413 mg, 500 umol), react under nitrogen protection at 20°C for 2 hours. LCMS detected the end of the reaction.
• Step 3 (E)-4-(4-(3,5-difluoro-4-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoro) ethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)phenyl)piperazin-1-yl)-N,N - Synthesis of dimethylbut-2-enamide
• Example 42 3-(4-((2-(4-(3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-tri Fluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)ethyl)piperidine Azin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 42)
• Step 1 4-(2-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoroethyl)-2,3,6, Synthesis of 7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester
• Step 3 Synthesis of 3-(4-((2-bromoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
• Step 4 3-(4-((2-(4-(3-((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-trifluoro) ethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)ethyl)piperazine Synthesis of -1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
• Example 43 Similar to the synthetic route of the previous Example 42, the following Example 43 was synthesized by selecting the corresponding reactants and the synthetic methods known to those skilled in the art.
• Example 43 3-(4-((2-(4-(3-(((6-((6S,8R)-8-methyl-2-oxo-7-(2,2,2-tris) Fluoroethyl)-2,3,6,7,8,9-hexahydrooxazolo[5,4-f]isoquinolin-6-yl)pyridin-3-yl)oxy)propyl)piperidine Azin-1-yl)ethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 43)
• AZD9496 catalog number: HY-12870
• AZD9833 catalog number: HY-136255
• tamoxifen catalog number: HY-13757A
• Comparative Compound 1 chemical structure: ( 6S,8R)-6-(2,6-Difluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-7-(2 -Fluoro-2-methylpropyl)-8-methyl-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinoline) using the example in WO2017/182493A1 1 prepared by the method.
• X is the "665 value to 615 value” for each concentration.
• Min is the mean value of "665 to 615" with the addition of 0.2 mM positive control compound and 5 nl of 3 nM (1.5 nM) estradiol.
• Max is the "665 value to 615 value” average of DMSO and 5nl 3nM (1.5nM) estradiol. Import the data into Graphpad Prism and use Log(agonist) vs.response--variable slope for curve fitting.
• Example 1 9.00 100.2
• Example 9 21.6 100.1
• Example 12 15.6 100.3
• Example 14 40.3 100.2
• Example 25 11.4 100.8
• Example 30 8.85 99.8
• Example 31 45.6 100.9
• Example 32 14.7 100.3
• Example 33 11.8 99.9
• Example 34 19.4 100.2 AZD9833 62.0 99.8 Tamoxifen 578.1 100.4
• Human breast cancer cells MCF-7 (HTB-22, purchased from ATCC) were seeded in 96-well plates in medium containing 10% FBS (Gibco, 10099-141), 1% pyruvate (Sigma, S8636), 1% Non-essential amino acids (Sigma, M7145) in MEM (Hyclone, SH30024.01B) medium, seeded at a density of 4,000 cells/well, and cells were cultured at 37°C, 5% CO 2 .
• Compounds were prepared as 20 mM stock solutions, serially diluted in 100% DMSO (Sigma, D2650) to a final concentration of 1000, and then diluted 20-fold in medium containing 2% FBS.
• Example 1 0.39
• Example 9 0.19
• Example 10 0.20
• Example 11 0.38
• Example 12 0.49
• Example 13 0.30
• Example 14 0.44
• Example 16 0.80
• Example 25 0.24
• Example 26 0.55
• Example 27 1.63
• Example 28 0.40
• Example 29 0.71
• Example 30 0.21
• Example 31 0.85
• Example 32 0.39
• Example 33 0.39
• Example 34 0.19
• Example 35 0.82
• Example 37 0.61
• Example 39 0.49
• Example 43 0.69 AZD9496* 3.84 AZD9833* 2.45 Tamoxifen* 274.50 Comparative Compound 1* 2.68
• This test example uses ER ⁇ DuoSet IC ELISA Kit (R&D, DYC5715) to detect the degradation of ER ⁇ by compounds.
• human breast cancer cells MCF-7 (source as above) were inoculated in 24-well plates; the medium was 10% activated carbon-treated FBS (Tocyto, UT61204), 1% pyruvate, and 1% non-essential amino acids.
• FBS Tocyto, UT61204
• 1% pyruvate 1% non-essential amino acids.
• MEM medium seeding density was 150,000 cells/well; cells were cultured at 37°C, 5% CO2 for 24 hours.
• the compounds to be tested were serially diluted and added to 24-well plates containing cells. Cells were incubated for 24 hours at 37°C, 5% CO2. ERa capture antibody was diluted to 1 ⁇ g/ml with PBS (Corning, 21-040-CVR), added at 100 ⁇ L/well to a 96-well plate, sealed and coated overnight at room temperature.
• the coated 96-well plate was washed three times with PBS, 300 ⁇ L of blocking solution (R&D, DY995) was added to each well, and the plate was blocked at room temperature for 1 hour.
• the 24-well plate was washed once with PBS, the residual liquid was removed, and 60 ⁇ L of lysate (6M urea (Sigma, U5378), 1 mM EDTA (Sigma, E9884), 0.5% TritonX-100 (Sigma, T8787), 1 mM urea (Sigma, T8787), 1 mM lysis buffer) was added to each well.
• the T0 plate sample was first added with 600 ⁇ L of stop solution (acetonitrile: methanol (95:5, v/v) solution containing 100 ng/mL tolbutamide (Sigma, T0891)), and then NADPH regeneration system working solution was added.
• stop solution acetonitrile: methanol (95:5, v/v) solution containing 100 ng/mL tolbutamide (Sigma, T0891)
• test product supernatant was diluted into 200 ⁇ L of aqueous solution containing 0.3% formic acid for LC-MS/MS analysis, and 100 ⁇ L of the reference product supernatant was diluted to 300 ⁇ L of pure water was used for LC-MS/MS analysis and calculated according to the following formula:

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